Stem cells, immortality, and the evolution of metastatic properties in breast cancer: telomere maintenance mechanisms and metastatic evolution.

Breast cancer is the most significant cause of cancer-related death in women around the world. The vast majority of breast cancer-associated mortality stems from metastasis, which remains an incurable disease state. Metastasis results from evolution of clones that possess the insidious properties required for dissemination and colonization of distant organs. These clonal populations are descended from breast cancer stem cells (CSCs), which are also responsible for their prolonged maintenance and continued evolution. Telomeres impose a lifespan on cells that can be extended when they are actively elongated, as occurs in CSCs. Thus, changes in telomere structure serve to promote the survival of CSCs and subsequent metastatic evolution. The selection of telomere maintenance mechanism (TMM) has important consequences not only for CSC survival and evolution, but also for their coordination of various signaling pathways that choreograph the metastatic cascade. Targeting the telomere maintenance machinery may therefore provide a boon to the treatment of metastatic breast cancer. Here we review the two major TMMs and the roles they play in the development of stem and metastatic breast cancer cells. We also highlight current and future approaches to targeting these mechanisms in clinical settings to alleviate metastatic breast cancers.